Pyridine matrix metalloproteinase inhibitors

ABSTRACT

Selective MMP-13 inhibitors are pyridine derivatives of the formula                  
 
or a pharmaceutically acceptable salt thereof,
 
wherein:
     R 1  and R 2  independently are hydrogen, halo, hydroxy, C 1 –C 6  alkyl, C 1 –C 6  alkoxy, C 2 –C 6  alkenyl, C 2 –C 6  alkynyl, NO 2 , NR 4 R 5 , CN, or CF 3 ;   E is independently O or S;   A and B independently are OR 4  or NR 4 R 5 ;   R 4  and R 5  independently are H, C 1 –C 6  alkyl, C 2 –C 6  alkenyl, C 2 –C 6  alkynyl, (CH 2 ) n  aryl, (CH 2 ) n  cycloalkyl, (CH 2 ) n  heteroaryl, or R 4  and R 5  when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S, or NH, and optionally substituted or unsubstituted;   n is an integer of from 0 to 6.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/071,073, filed Feb. 8, 2002, now U.S. Pat. No. 6,881,743, whichclaims benefit of priority from U.S. provisional application No.60/268,781, filed Feb. 14, 2001.

FIELD OF THE INVENTION

This invention relates to pyridine derivatives that inhibit matrixmetalloproteinase enzymes and thus are useful for treating diseasesresulting from tissue breakdown such as heart disease, multiplesclerosis, osteo- and rheumatoid arthritis, atherosclerosis, andosteoporosis.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (sometimes referred to as MMPs) are naturallyoccurring enzymes found in most mammals. Over-expression and activationof MMPs or an imbalance between MMPs and inhibitors of MMPs have beensuggested as factors in the pathogenesis of diseases characterized bythe breakdown of extracellular matrix or connective tissues.

Stromelysin-1 and gelatinase A are members of the matrixmetalloproteinases (MMP) family. Other members include fibroblastcollagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11),matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme(TACE), and other newly discovered membrane-associated matrixmetalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A.,Yamamoto E., and Seiki M., Nature, 1994; 370:61–65). These enzymes havebeen implicated with a number of diseases which result from breakdown ofconnective tissue, including such diseases as rheumatoid arthritis,osteoarthritis, osteoporosis, periodontitis, multiple sclerosis,gingivitis, corneal epidermal and gastric ulceration, atherosclerosis,neointimal proliferation which leads to restenosis and ischemic heartfailure, and tumor metastasis. A method for preventing and treatingthese and other diseases is now recognized to be by inhibiting matrixmetalloproteinase enzymes, thereby curtailing and/or eliminating thebreakdown of connective tissues that results in the disease states.

There is a catalytic zinc domain in matrix metalloproteinases that istypically the focal point for inhibitor design. The modification ofsubstrates by introducing zinc-chelating groups has generated potentinhibitors such as peptide hydroxamates and thiol-containing peptides.Peptide hydroxamates and the natural endogenous inhibitors of MMPs(TIMPs) have been used successfully to treat animal models of cancer andinflammation. MMP inhibitors have also been used to prevent and treatcongestive heart failure and other cardiovascular diseases, U.S. Pat.No. 5,948,780.

A major limitation on the use of currently known MMP inhibitors is theirlack of specificity for any particular enzyme. Recent data hasestablished that specific MMP enzymes are associated with some diseases,but have no apparent effect on other diseases. The MMPs are generallycategorized based on their substrate specificity; indeed, thecollagenase subfamily of MMP-1, MMP-8, and MMP-13 selectively cleavenative interstitial collagens, and thus are associated only withdiseases linked to such interstitial collagen tissue. This is evidencedby the recent discovery that MMP-13 alone is over expressed in breastcarcinoma, while MMP-1 alone is over expressed in papillary carcinoma(see Chen et al., J. Am. Chem. Soc., 2000; 122:9648–9654).

There appears to be few selective inhibitors of MMP-13 reported. Acompound named WAY-170523 has been reported by Chen et al., supra.,2000, and a few other compounds are reported in PCT InternationalApplication Publication Number WO 01/63244 A1, as allegedly selectiveinhibitors of MMP-13. Further, U.S. Pat. No. 6,008,243 disclosesinhibitors of MMP-13. However, no selective or nonselective inhibitor ofMMP-13 has been approved and marketed for the treatment of any diseasein any mammal. Accordingly, the need continues to find new low molecularweight compounds that are potent and selective MMP inhibitors, and thathave an acceptable therapeutic index of toxicity/potency to make themamenable for use clinically in the prevention and treatment of theassociated disease states. An object of this invention is to provide agroup of selective MMP-13 inhibitor compounds characterized as beingisophthalic acid derivatives.

SUMMARY OF THE INVENTION

This invention provides a method for inhibiting matrix metalloproteinaseenzymes, and especially MMP-13, using a pyridine compound. The inventionis more particularly directed to a method for inhibiting MMP enzymes ina mammal, comprising administering to the mammal an MMP inhibitingamount of a compound defined by Formula I

or a pharmaceutically acceptable salt thereof,wherein:

-   R¹ and R² independently are hydrogen, halo, hydroxy, C₁–C₆ alkyl,    C₁–C₆ alkoxy, C₂–C₆ alkenyl, C₂–C₆ alkynyl, NO₂, NR⁴R⁵, CN, or CF₃;-   E is independently O or S;-   A and B independently are OR⁴ or NR⁴R⁵;-   R⁴ and R⁵ independently are H, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆    alkynyl, (CH₂)_(n) aryl, (CH₂)_(n) cycloalkyl, (CH₂)_(n) heteroaryl,    or R⁴ and R⁵ when taken together with the nitrogen to which they are    attached complete a 3- to 8-membered ring, containing carbon atoms    and optionally containing a heteroatom selected from O, S, or NH,    and optionally substituted or unsubstituted;-   n is an integer from 0 to 6.

Another invention embodiment is a method of inhibiting MMP enzymes in amammal comprising administering to the mammal an MMP inhibiting amountof a compound of Formula II

-   or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are    as defined above, and each R⁴ independently is as defined above.

Another invention embodiment is a method of inhibiting MMP enzymes in amammal comprising administering to the mammal an MMP inhibiting amountof a compound of Formula III

-   or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are    as defined above, and each R⁴ and R⁵ independently are as defined    above.

Another invention embodiment is a method of inhibiting MMP enzymes in amammal comprising administering to the mammal an MMP inhibiting amountof a compound of Formula IV

-   or a pharmaceutically acceptable salt thereof, wherein n, R¹, and R²    are as defined above, and R⁶, R⁷, R⁸, and R⁹ independently are    hydrogen, halo, C₁–C₆ alkyl, C₁–C₆ alkoxy, nitro, or NH₂.

Another invention embodiment is a method of inhibiting MMP enzymes in amammal comprising administering to the mammal an MMP inhibiting amountof a compound of Formula V

-   or a pharmaceutically acceptable salt thereof, wherein n, R¹, and R²    are as defined above, and each Ar independently is aryl or Het,    wherein aryl is phenyl or substituted phenyl, and Het is an    unsubstituted or substituted heteroaryl group.

Compounds of Formulas I, II, III, IV, and V are provided as a furtherembodiment of this invention.

Another invention embodiment are compounds that are amides of Formula I,or a pharmaceutically acceptable salt thereof, wherein one or both of Aand B is NR⁴R⁵.

Another invention embodiment is a compound selected from:

-   Pyridine-3,5-dicarboxylic acid, (4-chloro-benzylamide),    [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (4-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (3-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carbomethoxy-benzylamide),    (3-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (3-pyridylmethylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (3-thiophenemethylamide);-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)    amide, [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl)    amide, [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)    amide, (4-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)    amide, (3-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)    ester;-   2-Methoxy-pyridine-3,5-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide];-   2-Ethoxy-pyridine-3,5-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide];-   2-Amino-pyridine-3,5-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide]; and-   2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide,-   2-Methoxy-pyridine-3,5-dicarboxylic acid bis-benzylamide,-   (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl    ester,-   (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid,-   Pyridine-2,4-dicarboxylic acid bis-(3-methoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2,4-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(4-chloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-benzylamide,-   Pyridine-2,4-dicarboxylic acid bis-[(naphthalen-1-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(2-p-tolyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(4-methoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-fluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(benzyl-ethyl-amide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3,4-dimethoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-phenoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(4-phenyl-butyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-fluoro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-chloro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2,4-dimethyl-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(2-o-tolyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-ethyl-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(2-phenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(1,2-diphenyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2,4-dichloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-[(biphenyl-2-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(3,4,5-trimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-chloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3,5-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3,4-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(ethyl-pyridin-4-ylmethyl-amide),-   Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-4-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-3-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-chloro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(pyridin-4-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-(3,5-bis-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2,3-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-difluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-difluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-(4-fluoro-3-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-methoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-ethoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-(3-chloro-4-fluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2,4-difluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(4-amino-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-methyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[bis-(4-methoxy-phenyl)-methyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(3,3-diphenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-[(1-methyl-3-phenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(3,4-dimethoxy-phenyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2-fluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-[(3-imidazol-1-yl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2-chloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(4-methyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(pyridin-3-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(4-ethoxy-phenyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(phenethyl-amide),-   Pyridine-2,4-dicarboxylic acid bis-[(thiophen-2-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(4-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-[(5-methyl-furan-2-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[1-(4-fluoro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-(2-amino-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-[(1-naphthalen-1-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-hydroxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[1-(3-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-trifluoromethyl-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide,-   Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide,-   Pyridine-2,4-dicarboxylic acid bis-(3,4-dichloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-[(2-ethoxy-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-bromo-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-2-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(2-thiophen-2-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(1H-indol-3-yl)-ethyl]-amide}; and-   Pyridine-2,4-dicarboxylic acid bis-(3,5-dichloro-benzylamide).

A further embodiment of this invention is a pharmaceutical composition,comprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof, admixed with a pharmaceutically acceptable carrier,excipient, or diluent.

Another invention embodiment is a pharmaceutical composition, comprisinga compound of any one of Formulas II, II, IV, and V, or apharmaceutically acceptable salt thereof, admixed with apharmaceutically acceptable carrier, excipient, or diluent.

Another invention embodiment is a pharmaceutical composition, comprisinga compound selected from:

-   Pyridine-3,5-dicarboxylic acid, (4-chloro-benzylamide),    [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (4-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (3-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carbomethoxy-benzylamide),    (3-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (3-pyridylmethylamide);-   Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide),    (3-thiophenemethylamide);-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)    amide, [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl)    amide, [(1,3-benzodioxol-5-ylmethyl)-amide];-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)    amide, (4-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)    amide, (3-methoxy-benzylamide);-   Pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)    ester;-   2-Methoxy-pyridine-3,5-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide];-   2-Ethoxy-pyridine-3,5-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide];-   2-Amino-pyridine-3,5-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide]; and-   2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide,-   2-Methoxy-pyridine-3,5-dicarboxylic acid bis-benzylamide,-   (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl    ester,-   (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid,-   Pyridine-2,4-dicarboxylic acid bis-(3-methoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2,4-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(4-chloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-benzylamide,-   Pyridine-2,4-dicarboxylic acid bis-[(naphthalen-1-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(2-p-tolyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(4-methoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-fluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(benzyl-ethyl-amide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3,4-dimethoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-phenoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(4-phenyl-butyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-fluoro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-chloro-phenyl)-ethyl]-amide-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2,4-dimethyl-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(2-o-tolyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-ethyl-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(2-phenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(1,2-diphenyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2,4-dichloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-[(biphenyl-2-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(3,4,5-trimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-chloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3,5-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3,4-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(ethyl-pyridin-4-ylmethyl-amide),-   Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-4-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-3-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-chloro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(pyridin-4-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-(3,5-bis-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2,3-dimethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(3-difluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-difluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-(4-fluoro-3-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-methoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-ethoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-(3-chloro-4-fluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2,4-difluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(4-amino-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-methyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[bis-(4-methoxy-phenyl)-methyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(3,3-diphenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-[(1-methyl-3-phenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(3,4-dimethoxy-phenyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2-fluoro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-[(3-imidazol-1-yl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(2-chloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-(4-methyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(pyridin-3-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(4-ethoxy-phenyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(phenethyl-amide),-   Pyridine-2,4-dicarboxylic acid bis-[(thiophen-2-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-(4-trifluoromethyl-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-[(5-methyl-furan-2-ylmethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[1-(4-fluoro-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-(2-amino-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-[(1-naphthalen-1-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-hydroxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethoxy-benzylamide),-   Pyridine-2,4-dicarboxylic acid    bis-([1-(3-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-propyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-methoxy-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-trifluoromethyl-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide,-   Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide,-   Pyridine-2,4-dicarboxylic acid bis-(3,4-dichloro-benzylamide),-   Pyridine-2,4-dicarboxylic acid bis-[(2-ethoxy-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-bromo-phenyl)-ethyl]-amide},-   Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-2-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid bis-[(2-thiophen-2-yl-ethyl)-amide],-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide),-   Pyridine-2,4-dicarboxylic acid    bis-{[2-(1H-indol-3-yl)-ethyl]-amide}; and-   Pyridine-2,4-dicarboxylic acid bis-(3,5-dichloro-benzylamide), or a    pharmaceutically acceptable salt thereof, admixed with a    pharmaceutically acceptable carrier, excipient, or diluent.

Another invention embodiment is a method for inhibiting an MMP-13 enzymein an animal, comprising administering to the animal an MMP-13inhibiting amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

A further embodiment is a method for treating a disease mediated by anMMP-13 enzyme, comprising administering to a patient suffering from sucha disease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

Another invention embodiment is a method for treating a disease mediatedby an MMP-13 enzyme, comprising administering to a patient sufferingfrom such a disease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein one or both of A and Bis NR⁴R⁵.

Another invention embodiment is a method for treating cancer, comprisingadministering to a patient having cancer and in need of treatment ananticancer effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

Another invention embodiment is a method for treating breast carcinoma,comprising administering to a patient having breast carcinoma and inneed of treatment an anticancer effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof.

Another invention embodiment is a method for treating osteoarthritis,comprising administering to a patient in need of treatment an effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

Another invention embodiment is a method for treating rheumatoidarthritis, comprising administering to a patient in need of treatment aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

Another invention embodiment is a method for treating inflammation,comprising administering to a patient in need of treatment an effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

Another invention embodiment is a method for treating heart failure,comprising administering to a patient in need of treatment an effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

A further embodiment is use of a compound of Formula I, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disease mediated by an MMP-13 enzyme.

Another invention embodiment is use of a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein one or both of A and Bis NR⁴R⁵, wherein R⁴ and R⁵ are as defined above, in the manufacture ofa medicament for the treatment of a disease mediated by an MMP-13enzyme.

Another invention embodiment is use of a compound of any one of FormulasII, III, IV, and V, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of a disease mediatedby an MMP-13 enzyme.

DETAILED DESCRIPTION OF THE INVENTION

The compounds to be used in the method of inhibiting MMP enzymesprovided by this invention are those defined by Formula I. In Formula I,R¹ to R⁹ include “C₁–C₆ alkyl” groups. These are straight and branchedcarbon chains having from 1 to 6 carbon atoms. Examples of such alkylgroups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, andn-hexyl. The alkyl groups can be substituted if desired, for instancewith groups such as hydroxy, amino, alkyl, aryl, and dialkylamino, halo,trifluoromethyl, carboxy, nitro, and cyano.

“Alkenyl” means straight and branched hydrocarbon radicals having from 2to 6 carbon atoms and one double bond and includes ethenyl,3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.

“Alkynyl” means straight and branched hydrocarbon radicals having from 2to 6 carbon atoms and one triple bond and includes ethynyl,3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.

“Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl group such ascyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl,adarnantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, andcyclopentyl. Such groups can be substituted with groups such as hydroxy,keto, and the like. Cycloalkyl groups can also be fused by two points ofattachment to other groups such as aryl and heteroaryl groups. Alsoincluded are rings in which 1 to 3 heteroatoms replace carbons. Suchgroups are termed “heterocyclyl,” which means a cycloalkyl group alsobearing at least one heteroatom selected from O, S, or NR², examplesbeing oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, andmorpholine.

“Alkoxy” refers to the alkyl groups mentioned above bound throughoxygen, examples of which include methoxy, ethoxy, isopropoxy,tert-butoxy, and the like. In addition, alkoxy refers to polyethers suchas —O—(CH₂)₂—O—OH₃, and the like.

“Acyl” means an R group that is an alkyl or aryl (Ar) group bondedthrough a carbonyl group, i.e., R—C(O)—, where R is alkyl or aryl. Forexample, acyl includes a C₁–C₆ alkanoyl, including substituted alkanoyl,wherein the alkyl portion can be substituted by NR⁴R⁵ or a carboxylic orheterocyclic group. Typical acyl groups include acetyl, benzoyl,isonicotinoyl, and the like.

The alkyl, alkenyl, alkoxy, and alkynyl groups described above areoptionally substituted, preferably by 1 to 3 groups selected from NR⁴R⁵,phenyl, substituted phenyl, naphthyl, thio C₁–C₆ alkyl, C₁–C₆ alkoxy,hydroxy, carboxy, C₁–C₆ alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl,and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, andsulfur. “Substituted nitrogen” means nitrogen bearing C₁–C₆ alkyl or(CH₂)_(n)Ph where n is 1, 2, or 3. Perhalo and polyhalo substitution isalso embraced.

Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl,pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl,2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl,methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl,4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl,3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and2-(4-methylpiperazinyl)ethyl.

Examples of substituted alkynyl groups include 2-methoxyethynyl,2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl),3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl,4-cyclobutyl-4-hexenyl, and the like.

Typical substituted alkoxy groups include aminomethoxy, acetoxymethoxy,trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,3-hydroxypropoxy, 6-carboxhexyloxy, and the like.

Further, examples of substituted alkyl, alkenyl, and alkynyl groupsinclude dimethylaminomethyl, carboxymethyl,4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl,4-morpholinobutyl, 4-tetrahydropyrinidylbutyl,3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,3-chlorophenylmethyl, and the like.

The terms “Ar” and “aryl” refer to unsubstituted and substitutedaromatic groups. Heteroaryl (Het) groups have from 4 to 9 ring atoms,from 1 to 4 of which are independently selected from the groupconsisting of O, S, and N. Preferred heteroaryl groups have 1 or 2heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclicaromatic ring systems are included in the definition of aryl andheteroaryl. Preferred substituent groups include alkyl, alkoxy, aryloxy,halo, amino, alkylamino, dialkylamino, CN, CF₃, thioalkyl, acyl andhydroxy. Typical aryl and heteroaryl groups include phenyl,3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl,benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl,3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl,indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole,thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole,benzo-2,1,3-oxadiazole, and the like.

Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3groups independently selected from the group consisting of alkyl,alkoxy, thio, thioalkyl, halo, hydroxy, —COOR⁷, trifluoromethyl, nitro,amino of the formula —NR⁴R⁵, and T(CH₂)_(m)QR⁴ or T(CH₂)_(m)CO₂R⁴wherein m is 1 to 6, T is O, S, NR⁴, N(O)R⁴, NR⁴R⁶Y, or CR⁴R⁵, Q is O,S, NR⁵, N(O)R⁵, or NR⁵R⁶Y wherein R⁴ and R⁵ are as described above, andR⁷ is hydrogen, alkyl, or substituted alkyl, for example, methyl,trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxygroups can be substituted as defined above. For example, typical groupsare carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, andalkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl,3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl,2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and3,5-dinitrophenyl.

Examples of NR⁴R⁵ groups include amino, methylamino, di-isopropylamino,acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutylamino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and3-carboxypropionyl amino. R⁴ and R⁵ can be taken together with thenitrogen to which they are attached to form a ring having 3 to 7 carbonatoms and 1, 2, or 3 heteroatoms selected from the group consisting ofnitrogen, substituted nitrogen, oxygen, and sulfur. Examples of suchcyclic NR⁴R⁵ groups include pyrrolidinyl, piperazinyl,4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl,pyrazinyl, morpholinyl, and the like.

“Halo” includes fluoro, chloro, bromo, and iodo.

The term “patient” means a mammal. Preferred patients include humans,cats, dogs, cows, horses, pigs, and sheep.

The term “animal” means a mammal. Preferred animals are include humans,rats, mice, guinea pigs, rabbits, monkeys, cats, dogs, cows, horses,pigs, and sheep.

The phrases “therapeutically effective amount” and “effective amount”are synonymous unless otherwise indicated, and mean an amount of acompound of the present invention that is sufficient to improve thecondition, disease, or disorder being treated. Determination of atherapeutically effective amount, as well as other factors related toeffective administration of a compound of the present invention to apatient in need of treatment, including dosage forms, routes ofadministration, and frequency of dosing, may depend upon the particularsof the condition that is encountered, including the patient andcondition being treated, the severity of the condition in a particularpatient, the particular compound being employed, the particular route ofadministration being employed, the frequency of dosing, and theparticular formulation being employed. Determination of atherapeutically effective treatment regimen for a patient is within thelevel of ordinary skill in the medical or veterinarian arts. In clinicaluse, an effective amount may be the amount that is recommended by theU.S. Food and Drug Administration, or an equivalent foreign agency.

The phrase “admixed” or “in admixture” means the ingredients so mixedcomprise either a heterogeneous or homogeneous mixture. Preferred is ahomogeneous mixture.

The phrases “pharmaceutical preparation” and “preparation” aresynonymous unless otherwise indicated, and include the formulation ofthe active compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Pharmaceuticalpreparations are fully described below.

The phrase “anticancer effective amount” means an amount of inventioncompound, or a pharmaceutically acceptable salt thereof, sufficient toinhibit, halt, or cause regression of the cancer being treated in aparticular patient or patient population. For example in humans or othermammals, an anticancer effective amount can be determined experimentallyin a laboratory or clinical setting, or may be the amount required bythe guidelines of the United States Food and Drug Administration, orequivalent foreign agency, for the particular cancer and patient beingtreated.

The phrase “MMP-13 inhibiting amount” means an amount of inventioncompound, or a pharmaceutically acceptable salt thereof, sufficient toinhibit an enzyme matrix metalloproteinase-13, including a truncatedform thereof, including a catalytic domain thereof, in a particularanimal or animal population. For example in a human or other mammal, anMMP-13 inhibiting amount can be determined experimentally in alaboratory or clinical setting, or may be the amount required by theguidelines of the United States Food and Drug Administration, orequivalent foreign agency, for the particular MMP-13 enzyme and patientbeing treated.

It should be appreciated that the matrix metalloproteinases include thefollowing enzymes:

-   -   MMP-1, also known as interstitial collagenase, collagenase-1, or        fibroblast-type collagenase;    -   MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;    -   MMP-3, also known as stromelysin or stromelysin-1;    -   MMP-7, also known as matrilysin or PUMP-1;    -   MMP-8, also known as collagenase-2, neutrophil collagenase, or        polymorphonuclear-type (“PMN-type”) collagenase;    -   MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;    -   MMP-10, also known as stromelysin-2;    -   MMP-11, also known as stromelysin-3;    -   MMP-12, also known as metalloelastase;    -   MMP-13, also known as collagenase-3;    -   MMP-14, also known as membrane-type (“MT”) 1-MMP or MT1-MMP;    -   MMP-15, also known as MT2-MMP;    -   MMP-16, also known as MT3-MMP;    -   MMP-17, also known as MT4-MMP;    -   MMP-18; and    -   MMP-19.

Other MMPs are known, including MMP-26, which is also known asmatrilysin-2.

One aspect of the present invention is a compound of Formula I, or apharmaceutically acceptable salt thereof, that is a selective inhibitorof the enzyme MMP-13. A selective inhibitor of MMP-13, as used in thepresent invention, is a compound that is ≧5 times more potent in vitroversus MMP-13 than versus at least one other matrix metalloproteinaseenzyme such as, for example, MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9,or MMP-14, or versus tumor necrosis factor alpha convertase (“TACE”). Apreferred aspect of the present invention is a compound that is aselective inhibitors of MMP-13 versus MMP-1.

Still other aspects of the present invention are compounds of Formula I,or a pharmaceutically acceptable salt thereof, that are selectiveinhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes, orversus TACE and 1, 2, 3, 4, 5, 6, or 7 other MMP enzymes. Other aspectsof the present invention are compounds of Formula I, or apharmaceutically acceptable salt thereof, that are ≧10 times, ≧20 times,≧50 times, ≧100 times, or ≧1000 times more potent versus MMP-13 thanversus at least one of any other MMP enzyme or TACE.

It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration, is within the level ofordinary skill in the pharmaceutical and medical arts, and is describedbelow.

The term “IC₅₀” means the concentration of test compound required toinhibit activity of a biological target, such as a receptor or enzyme,by 50%.

The phrase “catalytic domain” means the domain containing a catalyticzinc cation of the MMP enzyme, wherein the MMP enzyme contains 2 or moredomains. A catalytic domain includes truncated forms thereof that retainat least some of the catalytic activity of MMP-13 or MMP-13CD. Forexample, the collagenases, of which MMP-13 is a member, have beenreported to contain a signal peptide domain, a propeptide domain, acatalytic domain, and a hemopexin-like domain (Ye Qi-Zhuang, Hupe D.,Johnson L., Current Medicinal Chemistry, 1996; 3:407–418).

The phrase “a method for inhibiting MMP-13” includes methods ofinhibiting full length MMP-13, truncated forms thereof that retaincatalytic activity, including forms that contain the catalytic domain ofMMP-13, as well as the catalytic domain of MMP-13 alone, and truncatedforms of the catalytic domain of MMP-13 that retain at least somecatalytic activity.

It should be appreciated that it has been shown previously (YeQi-Zhuang, et al., 1996, supra) that inhibitor activity against acatalytic domain of an MMP is predictive of the inhibitor activityagainst the respective full-length enzyme.

The compounds to be used in the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

The compounds of Formula I may have chiral centers, and thus can existas racemic mixtures and individual enantiomers. All such isomeric formscan be used in the method of this invention and are provided as newcompounds.

The compounds of the invention are capable of further forming bothpharmaceutically acceptable formulations comprising salts, including butnot limited to acid addition and/or base salts, solvents and N-oxides ofa compound of the invention. This invention also provides pharmaceuticalformulations comprising a compound of the invention together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Allof these forms can be used in the method of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of theinvention include salts derived form inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic,phosphorus, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated arethe salts of amino acids such as arginate, gluconate, galacturonate, andthe like; see, for example, Berge et al., “Pharmaceutical Salts,” J. ofPharmaceutical Science, 1977; 66:1–19.

The acid addition salts of the basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base, andisolating the free base in the conventional manner. The free base formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metal hydroxides, or oforganic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Examples of suitable aminesare N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see,for example, Berge et al., supra., 1977.

The base addition salts of acidic compounds are prepared by contactingthe free acid form with a sufficient amount of the desired base toproduce the salt in the conventional manner. The free acid form may beregenerated by contacting the salt form with an acid and isolating thefree acid in a conventional manner. The free acid forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but otherwise the salts are equivalentto their respective free acid for purposes of the present invention.

The compounds of the present invention can be formulated andadministered in a wide variety of oral and parenteral dosage forms,including transdermal and rectal administration. All that is required isthat an MMP inhibitor be administered to a mammal suffering from adisease in an effective amount, which is that amount required to causean improvement in the disease and/or the symptoms associated with suchdisease. It will be recognized to those skilled in the art that thefollowing dosage forms may comprise as the active component, either acompound of the invention or a corresponding pharmaceutically acceptablesalt or solvate of a compound of the invention.

The invention compounds are prepared by methods well known to thoseskilled in the art of organic chemistry. The compounds of the inventionare prepared utilizing commercially available starting materials, orreactants that are readily prepared by standard organic synthetictechniques. A typical synthesis of the invention compounds of Formula Iis shown in Scheme 1 below. The first step in Scheme 1 comprisesreacting a diacid with a chlorinating reagent such as thionyl chlorideor oxalyl chloride in a nonprotic solvent such as dichloromethane (DCM)to give the diacid chloride. This acid chloride can then be reacted withan amine, NHR⁴R⁵, in excess or with an organic base such astriethylamine, to give a bis-amide of Formula I. Alternately, the acidchloride can be reacted with an alcohol, R⁴OH, in a nonprotic solventsuch as dichloromethane along with an organic or inorganic base such astriethylamine or potassium carbonate to give a bis-ester of Formula I.The bis-ester can in some circumstances be reacted with an amine,NHR⁴R⁵, at elevated temperatures to give a bis-amide of Formula I. Thediacid can also be reacted with an alkyl halide in a nonprotic solventcontaining an organic or inorganic base to give a bis-ester of FormulaI. A third sequence involves the reaction of the diacid withhydroxybenzotriazole, HOBt, and dicyclohexylcarbodiimide, DCC, and anamine, NHR⁴R⁵, in a solvent such as dimethylformamide, DMF, ordichloromethane to give a bis-amide of Formula I.

Compounds of Formula I have also been synthesized using combinatorialtechniques, Scheme 2. The diacid chloride is bound to a resin such asMarshall resin to give a bound acid chloride. This is then reacted withan amine, NHR⁴R⁵, in the presence of triethylamine in a solvent such asDCM to give a resin-bound amide. The resin is then cleaved by reactionwith an amine, NHR⁴R⁵, in dioxane in the presence of an organic base togive a bis-amide of Formula I, wherein each R⁴ and R⁵ independently areas defined above.

The following detailed examples further illustrate the synthesis oftypical invention compounds of Formula I. The examples arerepresentative only, and are not to be construed as limiting theinvention in any respect.

EXAMPLE 1

Pyridine-2,4-dicarboxylic acid bis-(3-methoxy-benzylaride)

To a solution of 2,4-pyridinedicarboxylic acid (1.0 g, 6.0 mmol) inmethylene chloride (40 mL) was added 1-hydroxybenzotriazole hydrate(HOBt) (2.03 g, 15 mmol), 3-methoxy-benzyl amine (1.53 mL, 12.0 mmol)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC)(2.88 g, 15 mmol). The solution was stirred for 24 hours at roomtemperature and then evaporated at reduced pressure to give an oil. Theoil was partitioned between hot ethyl acetate and hot water. The organicphase was then washed with saturated sodium bicarbonate, water, andfinally brine. The organic phase was dried over magnesium sulfate andevaporated at reduced pressure to give an orange oil. This was purifiedby MPLC chromatography using silica gel and 1:1, hexane:ethyl acetate.The oil fractions shown by thin layer chromatography (tlc) to containthe major product were combined, and the solvent was removed byevaporation under reduced pressure to give 1.85 g (76%) of the titledcompound as a clear oil.

MS: M+1=406.1; Microanalysis (C₂₃H₂₃N₃O₄): Calculated (Calc'd): C=68.13;H=5.97; N=10.36. Found: C=68.05; H=5.97; N=10.23.

Examples 2–9 were prepared by following the same general proceduredetailed in Example 1.

EXAMPLE 2

Pyridine-3,5-dicarboxylic acid bis-(4-chloro-benzylamide); mp 224–225°C.

EXAMPLE 3

Pyridine-3,5-dicarboxylic acid bis-(3-chloro-benzylamide); mp 185–186°C.

EXAMPLE 4

2-Methoxy-pyridine-3,5-dicarboxylic acidbis-[(1,3-benzodioxol-5-ylmethyl)-amide];

MS: M+1=464.1; Microanalysis (C₂₄H₂₁N₃O₇.0.52 H₂O): Calcd: C=60.97;H=4.70; N=8.89. Found: C=60.92; H=4.33; N=8.83.

EXAMPLE 5

Pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester;

mp 113–114° C.

EXAMPLE 6

Pyridine-3,5-dicarboxylic acid bis-(4-methoxy-benzylamide);

mp 224–225° C.

EXAMPLE 7

Pyridine-3,5-dicarboxylic acid bis-[(1,3-benzodioxol-5-ylmethyl)-amide];

mp 194–195° C.

EXAMPLE 8

Pyridine-2,4-dicarboxylic acid bis-[(1,3-benzodioxol-5-ylmethyl)-amide];

MS: M+1=434.1; Microanalysis (C₂₃H₁₉N₃O₆.1.06 H₂O): Calcd: C=61.05;H=4.70; N=9.29. Found: C=61.01; H=4.64; N=9.39.

EXAMPLE 9

Pyridine-3,5-dicarboxylic acid bis-(4-fluoro-benzylamide);

mp 216–218° C.

EXAMPLE 10

2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide

(a) 5-Benzylcarbamoyl-6-hydroxy-nicotinic acid

To a suspension of 5-Benzylcarbamoyl-6-hydroxy-nicotinic acid methylester in methanol (20 ml) was added 5.2 ml (5.2 mmol) 1N NaOH. Themixture was heated to 50° C. and stirred overnight. Additional 1N NaOHwas added (8.0 ml, 8.0 mmol). The mixture was heated to reflux for 6hours. The mixture was allowed to cool and was stirred overnight.Methanol was removed by concentrating at reduced pressure. The resultingresidue was dissolved in H₂O and extracted with diethyl ether. Theaqueous layer was acidified with 1M HCl and filtered. The solid productwas washed with water and dried at reduced pressure overnight at 55° C.1.2 g (85% yield). MS: m/z (APCI, AP+) 373.0 [M⁻]⁺. CHN Analysis: Calcd:C, 61.76; H, 4.44; N, 10.29. Found: C, 61.41; H, 4.42; N, 9.98.(b) 5-Benzylcarbamoyl-6-hydroxy-nicotinic acid methyl ester

To a mixture of 2-hydroxy-pyridine-3,5-dicarboxylic acid 5-methyl ester,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC.HCl0.49 g, 2.6 mmol), 1-hydroxybenzotriazole hydrate (HOBT 0.35 g, 2.6mmol), in dimethylformamide (10 ml) was added benzylamine 0.27 g (2.6mmol). The mixture was stirred overnight at room temperature. Water wasadded (20 ml), and the mixture was filtered. The solid product wasslurried in hot ethyl acetate to give 0.17 g (28% yield) of the titlecompound. MS: m/z (APCI, AP+) 287 [M⁻]⁺. CHN Analysis: C₁₅H₁₄N₂O₄⁻0.47H2O; Calcd: C, 61.12; H, 5.11; N, 9.50. Found: C, 61.17; H, 4.81;N, 9.71.(c) 2-Hydroxy-pyridine-3,5-dicarboxylic acid 5-methyl ester

To a suspension of 5.23 g (24.0 mmol) of 5-bromo-2-hydroxy-nicotinicacid in 100 ml methanol in a 300 cubic centimeter (cc) Teflon-gasketedstainless steal reactor was added triethyl amine (16.6 ml), followed bypalladium acetate (0.75 g, 3.31 mmol) and diphenylphosphino propane(DPPP, 2.13 g, 5.1 mmol). The reactor was flushed with carbon monoxidethen pressurized to 500 psi. The mixture was maintained at 100° C. for39.5 hours. The mixture was then cooled to room temperature, and thereaction mixture was filtered using methanol as the eluent. The filtratewas concentrated at reduced pressure. The residue was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was extracted once again with saturated aqueous sodiumbicarbonate. The combined aqueous layers were acidified usingconcentrated HCl. The resulting solid was filtered, washed two timeswith water, slurried in hot ethyl acetate, and filtered. The product wasdried overnight in a vacuum oven at 55° C. 2.8 g 59% yield. MS: m/z(APCI, AP+) 198 [M⁻]⁺. CHN Analysis: Calcd: C, 48.74; H, 3.58; N, 7.10.Found: C, 48.99; H, 3.45; N, 7.35.(d) 5-Bromo-2-hydroxy-nicotinic acid

To a suspension of 5.0 g (35.9 mmol) of 2-hydroxy-nicotinic acid in 30ml acetic acid was added dropwise 7.5 g (46.7 mmol) bromine. The mixturewas maintained at 70–80° C. overnight. The mixture was cooled and theacetic acid was removed under reduced pressure. Water (100 ml) was addedand the product was filtered and washed with water (3×100 ml). The solidwas dried in a vacuum oven at 65° C. for 48 hours to provide 6.1 g (78%yield) of the title compound.

MS: m/z (APCI, AP+) 219.0 [M⁻]⁺. CHN Analysis: Calcd: C, 33.06; H, 1.85;N, 6.42. Found: C, 32.91; H, 1.78; N, 6.23.

(e) 2-oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide

To a suspension of 5-benzylcarbamoyl-6-hydroxy-nicotinic acid 1.0 (3.67mmol), EDAC.HCl 0.84 g (4.4 mmol), HOBT 0.59 g (4.4 mmol), indimethylformamide (20 mL) was added benzylamine 0.47 g (4.4 mmol). Themixture was stirred overnight at room temperature. Water (20 mL) wasadded, and the reaction mixture was filtered. The solid product was thenslurried in hot ethyl acetate. 1.1 g (81% yield). MS: m/z (APCI, AP+)362.2 [M⁻]⁺. CHN Analysis: Calcd: C, 69.79; H, 5.30; N, 11.63. Found: C,69.49; H, 5.38; N, 11.64.

EXAMPLE 11

2-Methoxy-pyridine-3,5-dicarboxylic acid bis-benzylamide

To a solution of 0.5 g (1.4 mmol)2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide in 10mL of N,N-dimethylformamide (DMF) was added 0.25 g (1.9 mmol)diisopropylethylamine amine followed by 0.19 g (1.4 mmol) iodomethane.The resulting mixture was stirred overnight at room temperature. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×20 mL). The combined organic extracts were washed with saturatedaqueous NaCl solution, and dried over MgSO₄. The product wascrystallized from ethyl acetate, providing 0.24 g (46% yield) of thetitle compound. MS: m/z (APCI, AP+) 376.3 [M⁻]⁺. CHN Analysis: Calcd: C,70.38; H, 5.64; N, 11.19. Found: C, 70.05; H, 5.49; N, 10.89.

EXAMPLE 12

(3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl ester

To a solution of 0.5 g (1.4 mmol)2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide in 10mL DMF was added 0.25 g (1.9 mmol) diisopropylethylamine followed by0.27 g (1.4 mmol) tert-butyl bromo acetate. The resulting mixture wasstirred overnight at room temperature, then diluted with water andextracted with ethyl acetate (2×20 ml). The combined organic extractswere washed with saturated aqueous NaCl solution, and dried over MgSO₄.The product was crystallized from ethyl acetate to provide 0.37 g (56%yield) of the title compound. MS: m/z (APCI, AP+) 476.3 [M⁻]⁺. CHNAnalysis: Calcd: C, 68.20; H, 6.15; N, 8.84. Found: C, 67.81; H, 6.18;N, 8.69.

EXAMPLE 13

(3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid

A solution of 0.25 g (0.53 mmol)(3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl esterin 10 ml 50% trifluoroacetic acid in CHCl₃ was stirred for 3 hours atroom temperature. The reaction mixture was then concentrated at reducedpressure to obtain a solid. The solid was slurried in ethyl acetate,filtered, washed with ethyl acetate, and then dried at 55° C. at reducedpressure overnight. 0.15 g (68% yield) of the title compound. MS: m/z(APCI, AP+) 420 [M⁻]⁺. CHN Analysis: Calcd: C, 65.86; H, 5.05; N, 10.02.Found: C, 65.73; H, 5.08; N, 9.86.

EXAMPLE 14

General Procedures to Prepare Invention Compounds in the CombinatorialArray

Resin Loading

Marshall resin (15.2 g, 21.25 mmol) was swollen in dichloromethane (DCM)(300 mL) in a 500-mL resin tube. This process was slightly exothermic,and caused the DCM to nearly boil. Once the mixture cooled, the tube wascapped, and agitated slowly for 5 minutes, with frequent venting. TheDCM was then decanted. This wash was repeated two additional times. Theresin was then resuspended in DCM (300 mL) and triethylamine (TEA) (3.2g, 32 mmol, 1.5 eq) was added slowly. The resulting mixture was swirledfor 5 minutes, then isophthalic acid dichloride (17.2 g, 85 mmol, 4 eq)was added in one portion. The resin tube was capped and carefullysecured in a wrist shaker, and inverted for 36 hours.

After 36 hours, a slight darkening of the resin was noted. The reactionsolvent was drained and the resin washed three times with DCM (200 mL)and two times with diethyl ether (200 mL). The resin was dried in vacuofor 24 hours. Loading was determined both by weight gain and by totalchloride determination. (Nitrogen content showed <0.05% N and thereforethe absence of TEA.HCl). Typical loading was 1.1 mmol/g.

Resin Distribution

A Miniblock resin loader was calibrated for each resin used in theprotocol. The weight in milligram of resin added per well was recorded,and the number of millimoles per well of isophthalic acid dichloride wascalculated. Using this calibration and the loading for each resin, 0.15mmol of resin-bound isophthalic acid dichloride was distributed to eachreaction tube. The valve was then closed on the block.

Amine Solution Preparation

An “A” amine set (NHR⁴R⁵) was diluted to 0.5 M in DCM. A 0.2-M solutionof TEA in DCM (1.5 mL per reaction) was prepared. A 0.2-M solution ofTEA in dioxane was also prepared (1.5 mL per reaction). A “B” amine set(NHR⁴R⁵) was diluted to 0.5 M in dioxane.

Addition of Amine “A”

The TEA solution in DCM (1.5 mL) containing was added to each reactiontube. Next, using the Miniblock Map as a guide, the appropriate “A”amine solution (315 μL, 1.05 eq) was added. The block was shaken for 24hours, then placed on a filtration station without a collection blockand drained. The valve was closed, and 2 mL DCM was added. The block wasshaken for 2 minutes, and again drained. The reaction block was storedunder vacuum prior to use.

Addition of Amine “B” and Resin Cleavage:

The TEA/dioxane solution (1.5 mL) was added to each reaction tube. Next,using the Miniblock Map as a guide, the appropriate “B” amine solution(300 μL, 1.05 eq) was distributed. The reaction block was shaken for 72hours, then placed on a filtration station with a labeled collectionblock, and drained. The valve was closed and 2 mL DCM was added. Thereaction block was shaken for 2 minutes, then drained into collectiontubes.

Analysis

The products in the tubes may be identified by loop mass spectrometryafter first evaporating the DCM from the MS samples.

Concentrate

Concentrate the crude samples in the Genevac.

The following compounds of Examples 14.1 to 14.80, the structures ofwhich were confirmed by mass spectrometry, were prepared according tothe above-described combinatorial synthesis protocol.

-   14.1 Pyridine-2,4-dicarboxylic acid bis-(3-methoxy-benzylamide) APCI    (MS+1) 406.452.-   14.2 Pyridine-2,4-dicarboxylic acid    bis-[(1,3-benzodioxol-5-ylmethyl)-amide], APCI-(MS+1) 434.418.-   14.3 Pyridine-2,4-dicarboxylic acid bis-(2,4-dimethoxy-benzylamide)    APCI-(MS+1) 466.503.-   14.4 Pyridine-2,4-dicarboxylic acid bis-(4-chloro-benzylamide)    APCI-(MS+1) 415.29.-   14.5 Pyridine-2,4-dicarboxylic acid bis-benzylamide APCI-(MS+1)    346.4.-   14.6 Pyridine-2,4-dicarboxylic acid    bis-[(naphthalen-1-ylmethyl)-amide], APCI-(MS+1) 446.52.-   14.7 Pyridine-2,4-dicarboxylic acid bis-[(2-p-tolyl-ethyl)-amide],    APCI-(MS+1) 402.507.-   14.8 Pyridine-2,4-dicarboxylic acid bis-(4-methoxy-benzylamide)    APCI-(MS+1) 406.452.

14.9 Pyridine-2,4-dicarboxylic acid bis-(3-fluoro-benzylamide)APCI-(MS+1) 382.38.

-   14.10 Pyridine-2,4-dicarboxylic acid bis-(benzyl-ethyl-amide)    APCI-(MS+1) 402.507.-   14.11 Pyridine-2,4-dicarboxylic acid    bis-{[2-(3,4-dimethoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 494.557.-   14.12 Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-phenoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 558.647.-   14.13 Pyridine-2,4-dicarboxylic acid bis-[(4-phenyl-butyl)-amide],    APCI-(MS+1) 430.561.-   14.14 Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-methoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 434.505.-   14.15 Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-fluoro-phenyl)-ethyl]-amide}, APCI-(MS+1) 410.434.-   14.16 Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-chloro-phenyl)-ethyl]-amide}, APCI-(MS+1) 443.344.-   14.17 Pyridine-2,4-dicarboxylic acid    bis-{[2-(2,4-dimethyl-phenyl)-ethyl]-amide}, APCI-(MS+1) 430.561.-   14.18 Pyridine-2,4-dicarboxylic acid bis-[(2-o-tolyl-ethyl)-amide],    APCI-(MS+1) 402.507.-   14.19 Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-ethyl-phenyl)-ethyl]-amide}, APCI-(MS+1) 430.561.-   14.20 Pyridine-2,4-dicarboxylic acid bis-[(2-phenyl-propyl)-amide],    APCI-(MS+1) 402.507.-   14.21 Pyridine-2,4-dicarboxylic acid    bis-[(1,2-diphenyl-ethyl)-amide], APCI-(MS+1) 526.649.-   14.22 Pyridine-2,4-dicarboxylic acid bis-(2,4-dichloro-benzylamide),    APCI-(MS+1) 484.181.-   14.23 Pyridine-2,4-dicarboxylic acid    bis-[(biphenyl-2-ylmethyl)-amide], APCI-(MS+1) 498.595.-   14.24 Pyridine-2,4-dicarboxylic acid    bis-(3,4,5-trimethoxy-benzylamide), APCI-(MS+1) 526.555.-   14.25 Pyridine-2,4-dicarboxylic acid bis-(3-chloro-benzylamide),    APCI-(MS+1) 415.29.-   14.26 Pyridine-2,4-dicarboxylic acid    bis-(3,5-dimethoxy-benzylamide), APCI-(MS+1) 466.503.-   14.27 Pyridine-2,4-dicarboxylic acid    bis-(3,4-dimethoxy-benzylamide), APCI-(MS+1) 466.503.-   14.28 Pyridine-2,4-dicarboxylic acid    bis-(ethyl-pyridin-4-ylmethyl-amide), APCI-(MS+1) 404.483.-   14.29 Pyridine-2,4-dicarboxylic acid    bis-[(2-pyridin-4-yl-ethyl)-amide], APCI-(MS+1) 376.43.-   14.30 Pyridine-2,4-dicarboxylic acid    bis-[(2-pyridin-3-yl-ethyl)-amide], APCI-(MS+1) 376.43.-   14.31 Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-chloro-phenyl)-ethyl]-amide}, APCI-(MS+1) 443.344.-   14.32 Pyridine-2,4-dicarboxylic acid    bis-[(pyridin-4-ylmethyl)-amide], APCI-(MS+1) 348.376.-   14.33 Pyridine-2,4-dicarboxylic acid    bis-(3,5-bis-trifluoromethyl-benzylamide), APCI-(MS+1) 618.389.-   14.34 Pyridine-2,4-dicarboxylic acid    bis-(2,3-dimethoxy-benzylamide), APCI-(MS+1) 466.503.-   14.35 Pyridine-2,4-dicarboxylic acid    bis-(3-trifluoromethyl-benzylamide), APCI-(MS+1) 482.394.-   14.36 Pyridine-2,4-dicarboxylic acid    bis-(2-trifluoromethoxy-benzylamide), APCI-(MS+1) 514.392.-   14.37 Pyridine-2,4-dicarboxylic acid    bis-(3-difluoromethoxy-benzylamide), APCI-(MS+1) 478.412.-   14.38 Pyridine-2,4-dicarboxylic acid    bis-(2-difluoromethoxy-benzylamide), APCI-(MS+1) 478.412.-   14.39 Pyridine-2,4-dicarboxylic acid    bis-(4-fluoro-3-trifluoromethyl-benzylamide), APCI-(MS+1) 518.375.-   14.40 Pyridine-2,4-dicarboxylic acid bis-(2-methoxy-benzylamide),    APCI-(MS+1) 406.452.-   14.41 Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-ethoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 462.559.-   14.42 Pyridine-2,4-dicarboxylic acid    bis-(3-chloro-4-fluoro-benzylamide), APCI-(MS+1) 451.27.-   14.43 Pyridine-2,4-dicarboxylic acid bis-(2,4-difluoro-benzylamide),    APCI-(MS+1) 418.361.-   14.44 Pyridine-2,4-dicarboxylic acid bis-(4-amino-benzylamide),    APCI-(MS+1) 376.43.-   14.45 Pyridine-2,4-dicarboxylic acid bis-(2-methyl-benzylamide),    APCI-(MS+1) 374.454.-   14.46 Pyridine-2,4-dicarboxylic acid    bis-{[bis-(4-methoxy-phenyl)-methyl]-amide}, APCI-(MS+1) 618.698.-   14.47 Pyridine-2,4-dicarboxylic acid    bis-[(3,3-diphenyl-propyl)-amide], APCI-(MS+1) 554.702.-   14.48 Pyridine-2,4-dicarboxylic acid    bis-[(1-methyl-3-phenyl-propyl)-amide], APCI-(MS+1) 430.561.-   14.49 Pyridine-2,4-dicarboxylic acid    bis-[(3,4-dimethoxy-phenyl)-amide], APCI-(MS+1) 438.45.-   14.50 Pyridine-2,4-dicarboxylic acid bis-(2-fluoro-benzylamide),    APCI-(MS+1) 382.38.-   14.51 Pyridine-2,4-dicarboxylic acid    bis-[(3-imidazol-1-yl-propyl)-amide], APCI-(MS+1) 382.438.-   14.52 Pyridine-2,4-dicarboxylic acid bis-(2-chloro-benzylamide),    APCI-(MS+1) 415.29.-   14.53 Pyridine-2,4-dicarboxylic acid    bis-(2-trifluoromethyl-benzylamide), APCI-(MS+1) 482.394.-   14.54 Pyridine-2,4-dicarboxylic acid bis-(4-methyl-benzylamide),    APCI-(MS+1) 374.454.-   14.55 Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-methoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 434.505.-   14.56 Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-ethyl)-amide],    APCI-(MS+1) 374.454.-   14.57 Pyridine-2,4-dicarboxylic acid    bis-[(pyridin-3-ylmethyl)-amide], APCI-(MS+1) 348.376.-   14.58 Pyridine-2,4-dicarboxylic acid bis-[(4-ethoxy-phenyl)-amide],    APCI-(MS+1) 406.452.-   14.59 Pyridine-2,4-dicarboxylic acid bis-(phenethyl-amide),    APCI-(MS+1) 374.454.-   14.60 Pyridine-2,4-dicarboxylic acid    bis-[(thiophen-2-ylmethyl)-amide], APCI-(MS+1) 358.456.-   14.61 Pyridine-2,4-dicarboxylic acid    bis-(4-trifluoromethyl-benzylamide), APCI-(MS+1) 482.394.-   14.62 Pyridine-2,4-dicarboxylic acid    bis-[(5-methyl-furan-2-ylmethyl)-amide], APCI-(MS+1) 354.376.-   14.63 Pyridine-2,4-dicarboxylic acid    bis-{[1-(4-fluoro-phenyl)-ethyl]-amide}, APCI-(MS+1) 410.434.-   14.64 Pyridine-2,4-dicarboxylic acid bis-(2-amino-benzylamide),    APCI-(MS+1) 376.43.-   14.65 Pyridine-2,4-dicarboxylic acid    bis-[(1-naphthalen-1-yl-ethyl)-amide], APCI-(MS+1) 474.573.-   14.66 Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-hydroxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 406.452.-   14.67 Pyridine-2,4-dicarboxylic acid    bis-(3-trifluoromethoxy-benzylamide), APCI-(MS+1) 514.392.-   14.68 Pyridine-2,4-dicarboxylic acid    bis-{[1-(3-methoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 434.505.-   14.69 Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-propyl)-amide],    APCI-(MS+1) 402.507.-   14.70 Pyridine-2,4-dicarboxylic acid    bis-{[2-(2-methoxy-phenyl)-ethyl]-amide}, APCI-(MS+1) 434.505.-   14.71 Pyridine-2,4-dicarboxylic acid    bis-{[2-(3-trifluoromethyl-phenyl)-ethyl]-amide}, APCI-(MS+1)    510.448.-   14.72 Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide APCI-(MS+1)    398.476.-   14.73 Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide APCI-(MS+1)    398.476 Pyridine-2,4-dicarboxylic acid    bis-(3,4-dichloro-benzylamide), APCI-(MS+1) 484.18.-   14.74 Pyridine-2,4-dicarboxylic acid bis-[(2-ethoxy-ethyl)-amide],    APCI-(MS+1) 310.364.-   14.75 Pyridine-2,4-dicarboxylic acid    bis-{[2-(4-bromo-phenyl)-ethyl]-amide}, APCI-(MS+1) 532.246.-   14.76 Pyridine-2,4-dicarboxylic acid    bis-[(2-pyridin-2-yl-ethyl)-amide], APCI-(MS+1) 376.43.-   14.77 Pyridine-2,4-dicarboxylic acid    bis-[(2-thiophen-2-yl-ethyl)-amide], APCI-(MS+1) 386.51.-   14.78 Pyridine-2,4-dicarboxylic acid    bis-{[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide}, APCI-(MS+1)    512.579.-   14.79 Pyridine-2,4-dicarboxylic acid    bis-{[2-(1H-indol-3-yl)-ethyl]-amide}, APCI-(MS+1) 452.527.-   14.80 Pyridine-2,4-dicarboxylic acid bis-(3,5-dichloro-benzylamide),    APCI-(MS+1) 484.18.

The invention compounds of Formula I have been evaluated in standardassays for their ability to inhibit the catalytic activity of variousMMP enzymes. The assays used to evaluate the biological activity of theinvention compounds are well known and routinely used by those skilledin the study of MMP inhibitors and their use to treat clinicalconditions.

The assays measure the amount by which a test compound reduces thehydrolysis of a thiopeptolide substrate catalyzed by a matrixmetalloproteinase enzyme. Such assays are described in detail by Ye etal., in Biochemistry, 1992; 31(45):11231–11235, which is incorporatedherein by reference.

Thiopeptolide substrates show virtually no decomposition or hydrolysisat or below neutral pH in the absence of a matrix metalloproteinaseenzyme. A typical thiopeptolide substrate commonly utilized for assaysis Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt. A 100-μL assay mixture willcontain 50 mM of N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acidbuffer (“HEPES”) at pH 7.0, 10 mM CaCl₂, 100 μM thiopeptolide substrate,and 1 mM 5,5′-dithio-bis-(2-nitro-benzoic acid) (DTNB). Thethiopeptolide substrate concentration may be varied from, for example,10 to 800 μM to obtain Km and Kcat values. The change in absorbance at405 nm is monitored on a Thermo Max microplate reader (MolecularDevices, Menlo Park, Calif.) at room temperature (22° C.). Thecalculation of the amount of hydrolysis of the thiopeptolide substrateis based on E₄₁₂=13600 M⁻¹ cm⁻¹ for the DTNB-derived product3-carboxy-4-nitrothiophenoxide. Assays are carried out with and withoutmatrix metalloproteinase inhibitor compounds, and the amount ofhydrolysis is compared for a determination of inhibitory activity of thetest compounds.

Representative compounds have been evaluated for their ability toinhibit various matrix metalloproteinase enzymes. The results aresummarized in Tables 1 and 2 below. Table 1 below presents inhibitoryactivity for compounds from various classes. Table 2 summarizes the datafor the compounds that were prepared according to the combinatorialprotocol described in Example 14. In the tables, MMP-1 refers tofull-length interstitial collagenase; MMP-3 refers to the catalyticdomain of stromelysin-1; MMP-13 refers to the catalytic domain ofcollagenase 3. Test compounds were evaluated at various concentrationsto determine their respective IC₅₀ values. In Tables 1 and 2, the IC₅₀values are the nanomolar and micromolar concentrations, respectively, ofcompound required to cause a 50% inhibition of the hydrolytic activityof the respective enzyme.

TABLE 1 MMP-1 MMP-3 MMP-13 Example No. IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1Nt Nt 35 2 Nt Nt 100,000 3 Nt Nt 30,000 4 Nt Nt 230 5 Nt Nt 470 6 Nt Nt8,700 7 30,000 100,000 2,300 8 Nt Nt 14 9 Nt Nt 100,000 Nt = Not tested.

TABLE 2 Compound by Example Number With Corresponding IC50 Data MMP-13Example No. IC50 CD/Human (μM) 14.1 0.038 14.2 0.033 14.3 100 14.4 0.314.5 0.29 14.6 30 14.7 100 14.8 0.13 14.9 0.18 14.10 100 14.11 100 14.1230 14.13 100 14.14 100 14.15 100 14.16 100 14.17 100 14.18 100 14.19 3014.20 100 14.21 30 14.22 30 14.23 30 14.24 100 14.25 0.074 14.26 10014.27 100 14.28 100 14.29 100 14.30 100 14.31 100 14.32 2 14.33 10014.34 100 14.35 0.31 14.36 100 14.37 0.26 14.38 100 14.39 0.28 14.40 10014.41 100 14.42 0.04 14.43 100 14.44 70 14.45 100 14.46 30 14.47 3014.48 100 14.49 100 14.50 84 14.51 100 14.52 100 14.53 100 14.54 1.514.55 100 14.56 100 14.57 34 14.58 100 14.59 100 14.60 13 14.61 30 14.6288 14.63 100 14.64 100 14.65 30 14.66 30 14.67 4 14.68 100 14.69 10014.71 100 14.72 100 14.73 0.44 14.74 100 14.75 100 14.76 100 14.77 10014.78 30 14.79 30 14.80 30

The foregoing data establish that the invention compounds of theinvention are potent inhibitors of MMP enzymes and are especially usefuldue to their selective inhibition of MMP-13. Because of this potent andselective inhibitory activity, the invention compounds are especiallyuseful to treat diseases mediated by the MMP enzymes, and particularlythose mediated by MMP-13.

Administration of an invention compound of Formula I, or apharmaceutically acceptable salt thereof, to a mammal to treat thediseases mediated by MMP enzymes is preferably, although notnecessarily, accomplished by administering the compound, or the saltthereof, in a pharmaceutical dosage form.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I. The activecompound generally is present in a concentration of about 5% to about95% by weight of the formulation.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances that may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid that is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from 5% or 10% to about 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component, with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 1 to 1000 mg, preferably 10 to 100 mg accordingto the particular application and the potency of the active component.The composition can, if desired, also contain other compatibletherapeutic agents.

In therapeutic use as agents to inhibit a matrix metalloproteinaseenzyme for the treatment of atherosclerotic plaque rupture, aorticaneurism, heart failure, restenosis, periodontal disease, cornealulceration, cancer metastasis, tumor angiogenesis, arthritis, or otherautoimmune or inflammatory disorders dependent upon breakdown ofconnective tissue, the compounds utilized in the pharmaceutical methodof this invention are administered at a dose that is effective toinhibit the hydrolytic activity of one or more matrix metalloproteinaseenzymes. The initial dosage of about 1 mg/kg to about 100 mg/kg dailywill be effective. A daily dose range of about 25 mg/kg to about 75mg/kg is preferred. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages that are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired. Typicaldosages will be from about 0.1 mg/kg to about 500 mg/kg, and ideallyabout 25 mg/kg to about 250 mg/kg, such that it will be an amount thatis effective to treat the particular disease being prevented orcontrolled.

The following examples illustrate typical pharmaceutical compositionsprovided by the invention.

COMPOSITION EXAMPLE 1

Tablet Formulation

Ingredient Amount (mg) Compound of Example 1 25 Lactose 50 Cornstarch(for mix) 10 Cornstarch (paste) 10 Magnesium stearate (1%)  5 Total 100 

The pyridine amide of Example 1, lactose, and cornstarch (for mix) areblended to uniformity. The cornstarch (for paste) is suspended in 200 mLof water and heated with stirring to form a paste. The paste is used togranulate the mixed powders. The wet granules are passed through a No. 8hand screen and dried at 80° C. The dry granules are lubricated with the1% magnesium stearate and pressed into a tablet. Such tablets can beadministered to a human from one to four times a day for treatment ofatherosclerosis and arthritis.

COMPOSITION EXAMPLE 2

Preparation for Oral Solution

Ingredient Amount Compound of Example 4 400 mg Sorbitol solution (70%N.F.) 40 mL Sodium benzoate 20 mg Saccharin 5 mg Red dye 10 mg Cherryflavor 20 mg Distilled water q.s. 100 mL

The sorbitol solution is added to 40 mL of distilled water, and thepyridine amide of Example 4 is dissolved therein. The saccharin, sodiumbenzoate, flavor, and dye are added and dissolved. The volume isadjusted to 100 mL with distilled water. Each milliliter of syrupcontains 4 mg of invention compound.

COMPOSITION EXAMPLE 3

Parenteral Solution

In a solution of 700 mL of propylene glycol and 200 mL of water forinjection is suspended 20 g of the compound of Example 9. Aftersuspension is complete, the pH is adjusted to 6.5 with 1N sodiumhydroxide, and the volume is made up to 1000 mL with water forinjection. The formulation is sterilized, filled into 5.0-mL ampouleseach containing 2.0 mL, and sealed under nitrogen.

As matrix metalloproteinase inhibitors, the compounds of the inventionare useful as agents for the treatment of multiple sclerosis. They arealso useful as agents for the treatment of atherosclerotic plaquerupture, restenosis, periodontal disease, corneal ulceration, treatmentof burns, decubital ulcers, wound repair, heart failure, cancermetastasis, tumor angiogenesis, arthritis, and other inflammatorydisorders dependent upon tissue invasion by leukocytes.

It should be appreciated that in all invention embodiments describedabove or in the claims below, whenever an R group such as, for example,R¹, R², R³, R⁴, R⁵, or R⁶, or an n group is used more than once todefine an invention compound, each use of the R group is independent ofany other use of that same R group or, for that matter, any other Rgroup, unless otherwise specified.

1. A compound selected from: Pyridine-2,4-dicarboxylic acidbis-(2,4-dimethoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(4-chloro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-benzylamide; Pyridine-2,4-dicarboxylic acidbis-[(2-p-tolyl-ethyl)-amide]; Pyridine-2,4-dicarboxylic acidbis-(4-methoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(3-fluoro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(benzyl-ethyl-amide); Pyridine-2,4-dicarboxylic acidbis-{[2-(3,4-dimethoxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylicacid bis-{[2-(2-phenoxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylicacid bis-[(4-phenyl-butyl)-amide]; Pyridine-2,4-dicarboxylic acidbis-{[2-(4-methoxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-{[2-(2-fluoro-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-{[2-(3-chloro-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-{[2-(2,4-dimethyl-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylicacid bis-[(2-o-tolyl-ethyl)-amide]; Pyridine-2,4-dicarboxylic acidbis-{[2-(4-ethyl-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-(2,4-dichloro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(3,4,5-trimethoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(3,5-dimethoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(3,4-dimethoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-{[2-(4-chloro-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-(3,5-bis-trifluoromethyl-benzylamide); Pyridine-2,4-dicarboxylicacid bis-(2,3-dimethoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(3-trifluoromethyl-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(4-fluoro-3-trifluoromethyl-benzylamide); Pyridine-2,4-dicarboxylicacid bis-(2-methoxy-benzylamide); Pyridine-2,4-dicarboxylic acidbis-{[2-(3-ethoxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-(3-chloro-4-fluoro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(2,4-difluoro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(4-amino-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(2-methyl-benzylamide); Pyridine-2,4-dicarboxylic acidbis-{[bis-(4-methoxy-phenyl)-methyl]-amide}; Pyridine-2,4-dicarboxylicacid bis-[(3,4-dimethoxy-phenyl)-amide]; Pyridine-2,4-dicarboxylic acidbis-(2-fluoro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(2-chloro-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(2-trifluoromethyl-benzylamide); Pyridine-2,4-dicarboxylic acidbis-{[2-(3-methoxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-[(4-ethoxy-phenyl)-amide]; Pyridine-2,4-dicarboxylic acidbis-(phenethyl-amide); Pyridine-2,4-dicarboxylic acidbis-(4-trifluoromethyl-benzylamide); Pyridine-2,4-dicarboxylic acidbis-(2-amino-benzylamide); Pyridine-2,4-dicarboxylic acidbis-{[2-(4-hydroxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-{[2-(2-methoxy-phenyl)-ethyl]-amide}; Pyridine-2,4-dicarboxylic acidbis-{[2-(3-trifluoromethyl-phenyl)-ethyl]-amide};Pyridine-2,4-dicarboxylic acid bis-(3,4-dichloro-benzylamide);Pyridine-2,4-dicarboxylic acid bis-{[2-(4-bromo-phenyl)-ethyl]-amide};or Pyridine-2,4-dicarboxylic acid bis-(3,5-dichloro-benzylamide).
 2. Apharmaceutical composition, comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, diluent, or excipient.
 3. A methodfor treating osteoarthritis, comprising administering to a patient inneed of treatment an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 4. A method for treatingrheumatoid arthritis, comprising administering to a patient in need oftreatment an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 5. A method for treating heartfailure, comprising administering to a patient in need of treatment aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.